12P - The prognostic significance of BRAF mutations in early-stage colon cancer

Background

BRAF mutations are found in approximately 10% of colon cancers (CC) and are associated with poor prognosis in the context of metastatic disease. The most common BRAF mutation, V600E, predicts response to treatment with cetuximab + encorafenib +/- binimetinib in the metastatic setting. With the opening of the AO22004 and TRESBIEN trials that will test encorafenib-containing regimens for early-stage CC with BRAF V600E, there is renewed interest in better understanding the natural history of these cancers.

Methods

We performed a systematic review and meta-analysis of randomized controlled trials and retrospective studies from patients with early-stage BRAF mutant CC. Key inclusion criteria were: a diagnosis of stage 2 or stage 3 colon cancer with BRAF mutation. Patients who received neoadjuvant treatment, and patients with rectal cancers were excluded. The primary endpoints were overall survival (OS) and recurrence-free survival (RFS). A meta-analysis was performed with a random effects model that incorporated sample size, hazard ratio (HR) and 95% confidence intervals (CI).

Results

Of 206 studies that underwent full-text review, 6 randomized controlled trials and 3 additional retrospective studies were included in the final analysis that comprised a total of 7242 and 884 patients with wild-type and mutated BRAF, respectively. BRAF mutation was associated with shortened OS (HR 1.55, 95% CI 1.30-1.85, I²=48.2%) and RFS (HR 1.37, 95% CI 1.09-1.72, I²=78%) in the cohort at-large. This finding remains when analyses are constrained to include only microsatellite instability-low / stable (MSS/ MSI-L) / proficient mismatch repair (pMMR) (OS: HR 1.71, 95% CI 1.17-2.49, I²=47.9%, RFS: HR 1.45, 95% CI 1.22-1.72, I²=0%) but not those with microsatellite instability-high / unstable (MSI/ MSI-H) / deficient mismatch repair (dMMR) (OS: HR 0.67, 95% CI 0.27-1.67, RFS: HR 1.04, 95% CI 0.60-1.82, I²=36.4%).

Conclusions

BRAF mutation in early-stage CC is associated with inferior prognosis compared to BRAF wild-type, particularly in MSS/MSI-L/pMMR tumors. This finding will help optimize clinical trial design for this patient population.

Legal entity responsible for the study

The authors.

Funding

Pfizer.

Disclosure

P. Kavan: Financial Interests, Personal, Advisory Role: Roche Canada, Eisai, Merck, Bristol Myers Squibb, Novartis, Pfizer, Amgen, Taiho Pharmaceutical. A.A.N. Rose: Financial Interests, Personal, Other, Employment: Merck; Financial Interests, Personal, Advisory Role: EMD Serono, Advanced Accelerator Applications/Novartis; Financial Interests, Personal, Stocks/Shares: Merck; Financial Interests, Institutional, Funding: AstraZeneca Canada, Merck, Pfizer, Seagen; Financial Interests, Personal, Research Grant: Canadian Institutes of Health Research, Canadian Cancer Society, Conquer Cancer Foundation, Jewish General Hospital Foundation, TransMed Tech Institute, Canada Foundation for Innovation. K. Ma: Financial Interests, Personal, Other, Travel/Accommodation: Pfizer, Taiho Pharmaceutical, Eisai; Financial Interests, Personal, Other, Honoraria: Pfizer, Ipsen, Novartis, Amgen, Merck, Merck, Roche, Eisan. All other authors have declared no conflicts of interest.